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SELECTIVE FLUOROALKYLATIONS USING SULFUR AND
SILICON BASED REAGENTS
by
Ying Wang
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)
December 2007
Copyright 2007 Ying Wang

In chapter 1, the history of fluorine chemistry, properties and applications of fluorine-containing compounds, as well as the fluorination reactions are reviewed. Some of the landmark discoveries and accomplishments in the field of fluorine chemistry are mentioned. The important chemical and biological properties of fluorine and fluorinated compounds are described leading to the wide and versatile applications of fluorine compounds in industry. The fluorination reactions, including direct fluorinations and organofluorine building block fluorinations, are introduced. Indeed, fluorine chemistry has played a significant role in many technology fields and its future will remain bright.; In chapter 2, a facile and efficient nucleophilic substitution reactions (SN2) using difluoromethyl phenyl sulfone with primary alkyl halides, elemental halogens, perfluoroalkyl halides have been disclosed through the in situ-generated (benzenesulfonyl)difluoromethyl anion in the presence of a base. The obtained (benzenesulfonyl)difluoromethylalkanes are useful intermediates for the preparation of 1,1-difluoro-1-alkenes and difluoromethylalkanes. Thus, difluoromethyl phenyl sulfone acts as both "=CF2" and "CF2H" synthons.; In chapter 3, a general and efficient nucleophilic difluoromethylation of carbonyl compounds (both enolizable and non-enolizable aldehydes and ketones) with difluoromethyl phenyl sulfone has been achieved by using a nucleophilic (phenylsulfonyl)difluoromethylation-reductive desulfonylation strategy, which promises to be a highly useful synthetic tool for many potential applications.; In chapter 4, the nucleophilic substitution of difluoromethyl phenyl sulfone with aldimines has been reported, which allows a facile and efficient synthesis of beta-hydroxy-alpha, alpha-difluoro imines and alpha-difluoromethyl amines through the intermediates (benzenesulfonyl)difluoromethylated amines. The methodology provides convenient and efficient ways to introduce gem-difluoromethylene building block (-CF2-) and difluoromethyl group (-CF2H) into nitrogen-containing organic compounds with potential bioactivity.; In chapter 5, tetrakis(dimethylamino)ethylene (TDAE) promoted nucleophilic reactions of bromodifluoromethyl phenyl sulfone with aldehydes have been presented. The resulting (benzenesulfonyl)difluoromethylated alcohols can be further transformed into difluoromethyl substituted alcohols and 1,1-difluoro-1-alkenes via reductive desulfonylation and Julia olefinationrespectively.; In chapter 6, a fluoride-induced nucleophilic (phenylthio)difluoromethylation method using TMS-CF2SPh has been achieved. This new methodology efficiently transfers "PhSCF2" group into both enolizable and non-enolizable aldehydes and ketones to give the corresponding (phenylthio)difluoromethylated alcohols in good to excellent yields. Diphenyl disulfide can also be (phenylthio)difluoromethylated into PhSCF2SPh in high yield. The reaction with methylbenzoate, however, gives only low yield of (phenylthio)difluoromethyl phenyl ketone. The above-obtained PhSCF2-containing alcohols can be further transformed into difluoromethyl alcohols using an oxidation-desulfonylation procedure. This new type of nucleophilic (phenylthio)difluoromethylation methodology may have other potential applications in the medicinal and agrochemical fields.; In chapter 7, successful alkoxide-induced nucleophilic pentafluoroethylation and trifluoromethylation of imines, aldehydes, ketones and primary alkyl iodides have been presented by using pentafluoroethyl phenyl sulfone (PhSO2CF2CF3) and trifluoromethyl phenyl sulfone (PhSO2CF3). Remarkably, the chiral sulfinylimines, when subjected to this pentafluoroethylation and trifluoromethylation, gave high diastereoselectivity.; In chaper 8, Ruppert-Prakash reagent, (trifluoromethyl)trimethylsilane (TMSCF3), as a new source of singlet difluorocarbene at low temperature (-50 °C), has been explored to prepare gem-difluorocyclopropanes from the corresponding alkenes. The reaction took place in the presence of catalyst tetrabutylammonium triphenyldifluorosilicate (TBAT) and gave moderate to good yields of gem-difluorocyclopropanes from the electron rich alkenes: tetra-, tri-, and 1,1-dialkyl substituted alkenes.; In chapter 9, difluoromethyl phenyl sulfone (PhSO2CF2H) and bromodifluoromethyl phenyl sulfone (PhSO2CF2Br) are used as novel difluorocarbene reagents to react with phenols, which provide a beneficial way to introduce difluoromethoxy (OCF2H) building block into organic compounds.

SELECTIVE FLUOROALKYLATIONS USING SULFUR AND
SILICON BASED REAGENTS
by
Ying Wang
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)
December 2007
Copyright 2007 Ying Wang